Comparison of Fast-Progression, Hyperprogressive Disease, and Early Deaths in Advanced Non-Small-Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or Chemotherapy.

PURPOSE: Hyperprogressive disease (HPD), fast progression (FP), and early death (ED) have been described in 13.8%, 4.7%, and 5.6% and in 5.1%, 2.8%, and 6.8%, respectively, of patients with non-small-cell lung cancer (NSCLC) treated with single-agent programmed cell death ligand 1 inhibitors (ICI) or chemotherapy, respectively. Whether FP/ED and HPD represent overlapping patterns is unknown. PATIENTS AND METHODS: FP, ED, and HPD were retrospectively assessed in patients with NSCLC treated with single-agent ICI or chemotherapy. Eligibility required 2 computed tomography (CT) scans before and 1 CT scan during treatment. (1) HPD, (2) FP, (3) ED were defined as (1) RECIST version 1.1 progression at first CT scan and tumor growth rate variation per month > 50%, (2) ≥ 50% increase in the sum of the longest diameters of target lesions within 6 weeks from baseline, and (3) death as a result of radiologic progression within 12 weeks from baseline CT scan, respectively. RESULTS: Of 406 ICI-treated NSCLC, 56 patients (13.8%), 9 patients (2.2%), and 36 patients (8.8%) were HPD, FP, and ED, respectively. Eight (14.2%) and 20 (35.7%) of 56 patients with HPD were also FP and ED. ED significantly correlated with baseline Eastern Cooperative Oncology Group performance status ≥ 2 compared with HPD (33% v 13%, P = .02). Overall survival was significantly longer for HPD (3.4 months [95% CI, 2.7 to 4.0 months]) compared with FP (0.7 months [95% CI, 0.6 to 0.8 months]); HR, 0.18 [95% CI, 0.08 to 0.42]; P < .0001) and ED (1.4 months [95% CI, 1.3 to 1.6 months]); HR, 0.19 [95% CI, 0.11 to 0.34]); P < .0001), whereas it did not differ between FP and ED (HR, 1.3 [95% CI, 0.56 to 3.0]; P = .55). Of 59 patients with NSCLC treated with single-agent chemotherapy, the HPD, FP, and ED rates were 5.1%, 1.7%, and 6.7%, respectively. CONCLUSION: FP, ED, and HPD represent distinct progression patterns with limited overlap and different survival outcomes.

Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy.

Importance: Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown. Objectives: To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. Design, Setting, and Participants: In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required. Interventions: The tumor growth rate (TGR) before and during treatment and variation per month (ΔTGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with ΔTGR exceeding 50%. Main Outcomes and Measures: The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy. Results: Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3% (n = 188) were 65 years or older, 72.4% (n = 294) had nonsquamous histology, and 92.9% (n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7% (n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5% [35 of 56] vs 42.6% [149 of 350]; P = .006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P = .003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD. Conclusions and Relevance: Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.

Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non-Small Cell Lung Cancer.

IMPORTANCE: Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma. OBJECTIVE: To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non-small cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR). RESULTS: In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort. CONCLUSIONS AND RELEVANCE: Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.